Biology subjects

Benkhelifa-Ziyyat, S.

Publications and source records attributed to Benkhelifa-Ziyyat, S..

4 recordsLinked to original sources

bioRxiv2026

GDF5 as a Multimodal Protector of the Motor Unit in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis is characterized by the progressive dismantling of the motor unit. While "dying back" hypothesis suggests that peripheral neuromuscular dysfunction precedes motor neuron loss, the molecular mechanisms limiting endogenous compensatory responses remain poorly understood. We longitudinally examined neuromuscular decline and GDF5-SMAD1/5/8 signaling in SOD1G93A mice. Our findings revealed a translational checkpoint linked to the lncRNA Myoparr that suppresses GDF5 production at symptom onset. To overcome this deficit, we delivered AAV9-GDF5 at the symptomatic stage. GDF5 supplementation restored SMAD signaling balance, shifting the motor unit from a pro-atrophic TGF-{beta}-SMAD2/3 toward a pro-myogenic SMAD1/5 profile. Treatment preserved muscle mass, reduced mitochondrial reactive oxygen species, and maintained neuromuscular junction integrity, including peri-synaptic glial support. GDF5 also promoted molecular recovery of spinal MNs by enhancing homeostatic marker expression. Together, these findings identify GDF5 as a multimodal stabilizer of the motor unit and highlight its potential as therapeutic target in combinatorial strategies aimed at coupling motor unit stabilization with central neuroprotective interventions.

physiology↗

bioRxiv2025

Systemic Factors Affect Bone Health in SMA Type II Patients and a Mouse Model of SMA

Spinal muscular atrophy (SMA) is a rare developmental disorder affecting multiple tissues. Among the non-central nervous system tissues implicated in SMA is the skeletal system, including bone and cartilage. Low bone mineral density, increased numbers of fractures of the long bones and vertebra, hip pain, and scoliosis have been reported across the spectrum of SMA patients. While lack of ambulation likely contributes significantly to bone pathology, SMA patients have markedly lower bone density compared to other non-ambulatory patients with debilitating diseases such as Duchenne muscular dystrophy, suggesting that there is a cell-intrinsic contribution of SMN to bone homeostasis and function. Mouse models of SMA have also confirmed the presence of bone and cartilage phenotypes. These alterations frequently persist post-treatment. Recent advancements in therapeutic strategies, approved by both the FDA and the EMA, have represented a leap forward in the management of SMA. However, treatment gaps remain. Post-treatment, patients frequently face continued challenges with scoliosis, bone fractures, and persistent muscle weakness--conditions that underscore the urgent need for more comprehensive therapeutic strategies with combination therapies that can support skeletal health. To date, no molecular map exists of the changes that occur in SMA patient bone and cartilage, impeding the ability of finding targeted therapies. To address this clinical need, we profiled the transcriptome of the vertebral bone and cartilage in a cohort of 11 Type II SMA patients who were undergoing surgery for scoliosis correction and compared them to 7 idiopathic scoliosis and 2 DMD controls. Additionally, we characterized the skeletal health of a mouse model of type I SMA. We find that multisystemic factors including liver and muscle health affect the underlying SMA bone pathology. Specifically, we detect alterations in the balance between osteoclasts and osteoblasts, changes in PPAR{gamma} signaling, mitochondrial oxidative phosphorylation and fatty acid beta-oxidation, and alterations in the muscle-derived factor Irisin that play a role in overall SMA bone pathology.

genomics↗

bioRxiv2024

Early endosome disturbance and endolysosomal pathway dysfunction in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a lethal dystrophy characterized by the progressive loss of muscle fibers caused by mutations in DMD gene and absence of the dystrophin protein. While autophagy and lysosome biogenesis defects have been described in DMD muscles, the endosomal pathway has never been studied. Here, we showed that impaired lysosome formation is associated with altered acidification and reduced degradative function of the endolysosomal pathway in muscle cells derived from DMD patients. Our data demonstrated that early endosomes are increased in these cells as well as in muscle biopsies from DMD patients and two animal models of DMD, mdx mice and GRMD dogs. We determined that these abnormalities are due to the lack of dystrophin per se and could be correlated with disease progression and severity. We further identified an abnormal upregulation of the Rab5 GTPase protein, one key actor of early endosomal biogenesis and fusion, in the three DMD models which may underlie the endosomal defects. Finally, we demonstrated that Rab5 knock-down in human DMD muscle cells as well as dystrophin restoration in GRMD dogs, normalize Rab5 expression levels and rescue endosomal abnormalities. This study unveils a defect in a pathway essential for muscle homeostasis and for efficacy of adeno associated virus vectors and antisense oligonucleotides-mediated therapies.

pathology↗

bioRxiv2018

Clathrin plaques form mechanotransducing platforms

Large flat clathrin plaques are stable features of the plasma membrane associated with sites of strong adhesion suggesting that they could also play a role in force transduction. Here, we analyzed how clathrin plaques interact with the cytoskeleton and how they respond to mechanical cues in skeletal muscle myotubes. We show that branched actin networks surrounding clathrin plaques are directly regulated by dynamin 2, anchor intermediate filaments and sequester YAP at the plasma membrane. Dynamin 2, clathrin and desmin intermediate filaments are all required for basal YAP nucleocytoplasmic distribution and efficient nuclear translocation in response to mechanical stimuli. Dynamin 2 mutations that are responsible for centronuclear myopathy in humans disorganize the desmin network and deregulate YAP signaling both in vitro and in vivo. Thus, clathrin plaques and associated dynamin 2 are defined here as a new sensor conveying mechanical cues and integrate cell signaling with cytoskeletal regulation.

cell biology↗